Clinical Neurology and Neurosurgery 137 (2015) 102–104
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Case Report
Oneiric stupor in a 45-year-old nurse with rapidly progressive dementia: What is the diagnosis? Pattamon Panyakaew a , Jirada Sringean a , Roongroj Bhidayasiri a,b,∗ a Chulalongkorn Center of Excellence on Parkinson Disease & Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand b Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles 90095, USA
a r t i c l e
i n f o
Article history: Received 15 December 2014 Received in revised form 29 May 2015 Accepted 1 July 2015 Available online 3 July 2015
1. Introduction Oneiric stupor refers to the peculiar motor behavior, consisting of simple automatic gestures mimicking daily-life activities [1]. It is a useful diagnostic sign of agrypnic excitata, which is a term to account for the association of slow wave sleep loss (“agrypnia”), and autonomic and motor overactivation (“excitata”) [2]. Here we described the presence of oneiric stupor in association with progressive dementia, hallucinations, and ataxia in a 45-year-old nurse who had neither previous nor family history of neurological disorders. Neither brain MRI and an EEG nor serologic studies for autoimmune and paraneoplastic disorders revealed any significant findings. Here, we discuss movement disorder phenomenologies, reveal pathological diagnosis and discuss the approach to the clinical data. 2. Case report A 45-year-old anesthetic nurse was referred to us with a 6-month history of gait instability and cognitive complaints. However, her symptoms started five months earlier with persistent worry of her risk of developing hepatocellular carcinoma after being found to have benign liver mass. As a result, she was treated with the presumed diagnosis of depression with sertraline and olanzapine although her anxiety and insomnia continued to predominate. Her sleep was so disrupted that she slept in fragments
∗ Corresponding author at: Chulalongkorn Center of Excellence on Parkinson Disease & Related Disorders, Chulalongkorn University Hospital, 1873 Rama 4 Road, Bangkok 10330, Thailand. Tel.: +662 256 4000x2501; fax: +662 256 4630. E-mail addresses: [email protected], [email protected] (R. Bhidayasiri). http://dx.doi.org/10.1016/j.clineuro.2015.07.001 0303-8467/© 2015 Elsevier B.V. All rights reserved.
throughout the night. Moreover, there were times throughout the night when her husband thought that she was partially awake making different body gestures, including cycling of both legs, manipulating her pajamas, pointing to non-existent objects, and chewing movements without any vocalizations. Each episode lasted for a few minutes occurring several times a night and none of the reported gestures were violent. She was able to partially recall these acts although no reasons were given why she performed these complex behaviors. She was previously healthy and there was no significant family history of neurologic disorders. For the past six months, she found it increasingly difficult to concentrate on her duty as the anesthetic nurse. The symptoms progressed rapidly within the next few months to a point that she frequently forgot her recent activities and developed multiple episodes of word finding difficulties although remote memory was still preserved. She also noted intermittent episodes of horizontal diplopia in which ophthalmic surgery was undertaken without any significant improvement. Despite being on olanzapine, visual and auditory hallucinations spontaneously emerged manifesting as seeing children, and hearing Thai traditional songs. On admission, 11 months after symptoms onset, she was restless, confused, and disoriented. Her resting pulse rate was 102/min but the rest of her vital signs and general examination was unremarkable. Her mini mental status examination was 24 out of 30 (0 out of 3 in recall memory). Repetitive movements of both legs were observed in which she uncontrollably rub both feet together and repeatedly flex and extend both hips but not in synchrony (See video). Although she experienced sensation of inner restlessness, the movements did not relieve the symptoms. Propranolol at the dosage 30 mg daily significantly alleviated the movements. When her arms were outstretched, spontaneous myoclonus of both hands were observed. She also had bilateral dysdiadochokinesia
P. Panyakaew et al. / Clinical Neurology and Neurosurgery 137 (2015) 102–104
103
Fig. 1. A brain MRI was essentially unremarkable showing a few nonspecific T2 hyperintensities in bilateral frontal lobe (A). An EEG, performed while awake, showed mild diffuse cerebral dysfunction with preserved posterior dominant rhythm (B).
and was unable to sit unsupported and stand due to prominent truncal ataxia (See video). Routine laboratory investigations and CSF examinations were normal. Serum lactate, ceruloplasmin, and thyroid function tests were within normal limits. Serologic studies for HIV, autoimmune, and paraneoplastic disorders (including NMDAR, VGKC, CV2/CRMP5, ANNA1, PCA1, ANNA2, Ma2, amphiphysin and basal ganglia antibodies) were all negative. Brain MRI showed a few scattered T2 hyperintensities in both frontal lobes but otherwise unremarkable, including diffusion-weighted and apparent diffusion coefficient sequences (Fig. 1A). The EEG, performed while awaked, showed mild diffuse cerebral dysfunction (Fig. 1B). Specific CSF studies, including the 14-3-3 protein, neuron specific enolase, tau protein, and S100b were not performed. 3. Discussion The salient clinical findings in this case were rapidly progressive dementia associated with hallucinations, ataxia, and sleep disturbances. The initial symptom of disturbed vigilance later proceeded to affect attention, memory, and also executive function. Together with both visual and auditory hallucinations, her cognitive profiles suggest the involvement of limbic system. Resting tachycardia suggests the presence of autonomic hyperactivation. Although sleep disturbances were initially interpreted as part of her anxiety and depression, it became clear later that her cyclical organization of sleep was so disrupted occurring in association with nocturnal motor activity. Putting all the jigsaws together, the disease process is likely to affect thalamolimbic system in which the etiologic differential diagnosis include prion diseases, limbic encephalitis, and neuronal surface antibody syndromes. The latter two possibilities may occur as a result of autoimmune or paraneoplastic processes, but are less likely in our patient as the disease course was too rapid without relapses or clinical fluctuations. However, cases of
autoimmune encephalitis of paraneoplastic or non-paraneoplastic in origins have been reported to present as prion-like syndrome. In particular, patients with anti-Ma2 encephalitis in association with breast cancer may present with rapid cognitive and behavioral changes in association with movement and sleep disorders. Normal CSF examination and brain imaging make limbic encephalitis less likely. Different types of antibodies were also tested negative; thus, making the possibility of prion disorders high on the list. The spectrum of movement disorders in this case deserves further characterization. First is the presence of semipurposeful repetitive hip flexion-extension movements associated with foot and less frequent hand rubbing resembling akathisia. While akathisia in our case is likely to be induced by olanzapine, it may occur as part of the agitation or nervousness, a common behavioral feature in prion diseases [3]. Specifically, akathisia may occur as a continuum of motor hyperactivation as part of a syndrome named agrypnic excitata (AE), which is a term to account for the association of slow wave sleep loss (“agrypnia”), and autonomic and motor overactivation (“excitata”) in patients with fatal familial insomnia (FFI) [2]. Together with resting tachycardia, it supports the presence of both autonomic and motor hyperactivation. Second is the recurrence of automatic gestures mimicking daily activities throughout the night including cycling, adjusting her pajamas, and pointing to non-existent objects. This feature probably represents oneiric stupor (OS), a peculiar behavior but useful diagnostic sign of AE [1]. A non-violent feature and the tendency to emerge at various times throughout the night distinguish OS from REM behavioral disorder (RBD). Recent polysomnographic study suggests that OS represents a state of unresponsiveness associated with dream-like mentation and appropriate motor behavior arising in the context of a completely disorganized sleep structure [1]. In addition to FFI, OS has been described in a number of disorders, including Morvan syndrome, delirium tremens, and sporadic Creutzfeldt-Jakob disease (CJD) of the VV2 subtype [1,4]. The presence of truncal ataxia,
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P. Panyakaew et al. / Clinical Neurology and Neurosurgery 137 (2015) 102–104
cycle and other autonomic functions, which could then disconnect the limbic cortical areas that involved in the control of instinctive behavior, and cognitive functions. However, in the absence of a positive family history, which is noted to be between 12 and 88% depending on the mutation types, the diagnosis of FFI can be difficult because of atypical clinical features and low sensitivity of diagnostic tests (CSF, EEG, and MRI are often normal or revealed nonspecific changes.) [6,7]. When clinically suspicious, the presence of unusual neuropsychiatric or cognitive illnesses should prompt treating physicians to consider prion disorders in the differential diagnosis, and proceed with relevant genetic testing. Recently, a scheme for the clinical diagnosis of FFI with a specificity of at least 80% was developed, which includes three items of organic sleep disturbances, CJD-like symptoms/signs, and relatively disease-specific symptoms/signs to allow the clinical suspicious of FFI no later than in the middle of the disease course [6]. This scheme further reinforces the fact that the clinical diagnosis of FFI is possible based on the careful observation of the clinical course, supported by VPSG and PET findings if available, and finally confirmed by the presence of a PRNP mutation on the genetic test. Fig. 2. The PRNP gene sequencing showed a missense GAC → AAC mutation at codon 178 while no mutation at codon 129 (Met) was observed.
Conflict of interest The authors have no conflict of interest.
gait instability, and myoclonus, which are also common movement disorders observed in various prion disorders, including CJD, Gerstmann-Sträussler-Scheinker, and FFI, does not help distinguish between different forms of prion disorders. The profession as the anesthetic nurse raises a slight possibility of iatrogenic CJD but she worked in a major university hospital, which employs standard disinfection methods for surgical instruments and biological products. The presence of autonomic, motor overactivation in conjunction with OS favors the possibility of FFI. Video polysomnographic (VPSG) study would be helpful in confirming our suspicious of FFI by demonstrating disruption of sleep-wake rhythm consisting of the disappearance of spindle delta activities, and the persistence of stage 1 non-REM sleep. REM sleep may persist but fails to stabilize appearing in short recurrent episodes during stage 1 NREM sleep [5]. Unfortunately, the test was not undertaken in the patient as the VPSG facility was not available locally. Although helpful, not all reported FFI cases in the medical literature have VPSG as a part of the diagnostic work-up and once organic sleep disturbances are evident, VPSG may not be considered as obligatory [6]. The analysis of genomic DNA showed a missense GAC → AAC mutation at codon 178 of PRNP gene resulting in the D178N substitution while no mutation at codon 129 (Met) was identified (Fig. 2). The finding (D178N, 129M) is consistent with the diagnosis of FFI. 4. Conclusion Our case provided many interesting learning points. First, the symptoms of insomnia were initially overlooked or trivialize into manifestations of anxiety and depression. Frequently neglected, fluctuating diplopia was also reported to be one of the common early manifestations of FFI [6]. Together with autonomic overactivity manifested as tachycardia, the clinical features implicate the dysfunction of the thalamus in the regulation of wake-sleep
Acknowledgment This study was supported by the Ratchadapiseksompoj Endowment Fund of Chulalongkorn University (RES560530136 & RES560530137-HR), research unit grant RA57/119 of Chulalongkorn University. We would like to thank Dr. Chanin Limwongse for his assistance with the genetic sequencing for a PRNP mutation. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.clineuro.2015.07. 001 References [1] P. Guaraldi, G. Calandra-Buonaura, R. Terlizzi, P. Montagna, E. Lugaresi, P. Tinuper, P. Cortelli, F. Provini, Oneiric stupor: the peculiar behaviour of agrypnia excitata, Sleep Med. 12 (Suppl. 2) (2011) S64–S67. [2] E. Lugaresi, F. Provini, Agrypnia excitata: clinical features and pathophysiological implications, Sleep Med. Rev. 5 (2001) 313–322. [3] A. Thompson, A. MacKay, P. Rudge, A. Lukic, M.C. Porter, J. Lowe, J. Collinge, S. Mead, Behavioral and psychiatric symptoms in prion disease, Am. J. Psychiatry 171 (2014) 265–274. [4] C. La Morgia, P. Parchi, S. Capellari, R. Lodi, C. Tonon, R. Rinaldi, S. Mondini, F. Cirignotta, ‘Agrypnia excitata’ in a case of sporadic Creutzfeldt-Jakob disease VV2, J. Neurol Neurosurg. Psychiatry 80 (2009) 244–246. [5] E. Sforza, P. Montagna, P. Tinuper, P. Cortelli, P. Avoni, F. Ferrillo, R. Petersen, P. Gambetti, E. Lugaresi, Sleep-wake cycle abnormalities in fatal familial insomnia evidence of the role of the thalamus in sleep regulation, Electroencephalogr. Clin. Neurophysiol. 94 (1995) 398–405. [6] A. Krasnianski, P. Sanchez Juan, C. Ponto, M. Bartl, U. Heinemann, D. Varges, W.J. Schulz-Schaeffer, H.A. Kretzschmar, I. Zerr, A proposal of new diagnostic pathway for fatal familial insomnia, J. Neurol. Neurosurg. Psychiatry 85 (2014) 654–659. [7] G.G. Kovacs, M. Puopolo, A. Ladogana, M. Pocchiari, H. Budka, C. van Duijn, S.J. Collins, A. Boyd, A. Giulivi, M. Coulthart, N. Delasnerie-Laupretre, J.P. Brandel, I. Zerr, H.A. Kretzschmar, J. de Pedro-Cuesta, M. Calero-Lara, M. Glatzel, A. Aguzzi, M. Bishop, R. Knight, G. Belay, R. Will, E. Mitrova, Eurocjd. Genetic prion disease: the EUROCJD experience, Hum. Genet. 118 (2005) 166–174.
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Case Report
Oneiric stupor in a 45-year-old nurse with rapidly progressive dementia: What is the diagnosis? Pattamon Panyakaew a , Jirada Sringean a , Roongroj Bhidayasiri a,b,∗ a Chulalongkorn Center of Excellence on Parkinson Disease & Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand b Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles 90095, USA
a r t i c l e
i n f o
Article history: Received 15 December 2014 Received in revised form 29 May 2015 Accepted 1 July 2015 Available online 3 July 2015
1. Introduction Oneiric stupor refers to the peculiar motor behavior, consisting of simple automatic gestures mimicking daily-life activities [1]. It is a useful diagnostic sign of agrypnic excitata, which is a term to account for the association of slow wave sleep loss (“agrypnia”), and autonomic and motor overactivation (“excitata”) [2]. Here we described the presence of oneiric stupor in association with progressive dementia, hallucinations, and ataxia in a 45-year-old nurse who had neither previous nor family history of neurological disorders. Neither brain MRI and an EEG nor serologic studies for autoimmune and paraneoplastic disorders revealed any significant findings. Here, we discuss movement disorder phenomenologies, reveal pathological diagnosis and discuss the approach to the clinical data. 2. Case report A 45-year-old anesthetic nurse was referred to us with a 6-month history of gait instability and cognitive complaints. However, her symptoms started five months earlier with persistent worry of her risk of developing hepatocellular carcinoma after being found to have benign liver mass. As a result, she was treated with the presumed diagnosis of depression with sertraline and olanzapine although her anxiety and insomnia continued to predominate. Her sleep was so disrupted that she slept in fragments
∗ Corresponding author at: Chulalongkorn Center of Excellence on Parkinson Disease & Related Disorders, Chulalongkorn University Hospital, 1873 Rama 4 Road, Bangkok 10330, Thailand. Tel.: +662 256 4000x2501; fax: +662 256 4630. E-mail addresses: [email protected], [email protected] (R. Bhidayasiri). http://dx.doi.org/10.1016/j.clineuro.2015.07.001 0303-8467/© 2015 Elsevier B.V. All rights reserved.
throughout the night. Moreover, there were times throughout the night when her husband thought that she was partially awake making different body gestures, including cycling of both legs, manipulating her pajamas, pointing to non-existent objects, and chewing movements without any vocalizations. Each episode lasted for a few minutes occurring several times a night and none of the reported gestures were violent. She was able to partially recall these acts although no reasons were given why she performed these complex behaviors. She was previously healthy and there was no significant family history of neurologic disorders. For the past six months, she found it increasingly difficult to concentrate on her duty as the anesthetic nurse. The symptoms progressed rapidly within the next few months to a point that she frequently forgot her recent activities and developed multiple episodes of word finding difficulties although remote memory was still preserved. She also noted intermittent episodes of horizontal diplopia in which ophthalmic surgery was undertaken without any significant improvement. Despite being on olanzapine, visual and auditory hallucinations spontaneously emerged manifesting as seeing children, and hearing Thai traditional songs. On admission, 11 months after symptoms onset, she was restless, confused, and disoriented. Her resting pulse rate was 102/min but the rest of her vital signs and general examination was unremarkable. Her mini mental status examination was 24 out of 30 (0 out of 3 in recall memory). Repetitive movements of both legs were observed in which she uncontrollably rub both feet together and repeatedly flex and extend both hips but not in synchrony (See video). Although she experienced sensation of inner restlessness, the movements did not relieve the symptoms. Propranolol at the dosage 30 mg daily significantly alleviated the movements. When her arms were outstretched, spontaneous myoclonus of both hands were observed. She also had bilateral dysdiadochokinesia
P. Panyakaew et al. / Clinical Neurology and Neurosurgery 137 (2015) 102–104
103
Fig. 1. A brain MRI was essentially unremarkable showing a few nonspecific T2 hyperintensities in bilateral frontal lobe (A). An EEG, performed while awake, showed mild diffuse cerebral dysfunction with preserved posterior dominant rhythm (B).
and was unable to sit unsupported and stand due to prominent truncal ataxia (See video). Routine laboratory investigations and CSF examinations were normal. Serum lactate, ceruloplasmin, and thyroid function tests were within normal limits. Serologic studies for HIV, autoimmune, and paraneoplastic disorders (including NMDAR, VGKC, CV2/CRMP5, ANNA1, PCA1, ANNA2, Ma2, amphiphysin and basal ganglia antibodies) were all negative. Brain MRI showed a few scattered T2 hyperintensities in both frontal lobes but otherwise unremarkable, including diffusion-weighted and apparent diffusion coefficient sequences (Fig. 1A). The EEG, performed while awaked, showed mild diffuse cerebral dysfunction (Fig. 1B). Specific CSF studies, including the 14-3-3 protein, neuron specific enolase, tau protein, and S100b were not performed. 3. Discussion The salient clinical findings in this case were rapidly progressive dementia associated with hallucinations, ataxia, and sleep disturbances. The initial symptom of disturbed vigilance later proceeded to affect attention, memory, and also executive function. Together with both visual and auditory hallucinations, her cognitive profiles suggest the involvement of limbic system. Resting tachycardia suggests the presence of autonomic hyperactivation. Although sleep disturbances were initially interpreted as part of her anxiety and depression, it became clear later that her cyclical organization of sleep was so disrupted occurring in association with nocturnal motor activity. Putting all the jigsaws together, the disease process is likely to affect thalamolimbic system in which the etiologic differential diagnosis include prion diseases, limbic encephalitis, and neuronal surface antibody syndromes. The latter two possibilities may occur as a result of autoimmune or paraneoplastic processes, but are less likely in our patient as the disease course was too rapid without relapses or clinical fluctuations. However, cases of
autoimmune encephalitis of paraneoplastic or non-paraneoplastic in origins have been reported to present as prion-like syndrome. In particular, patients with anti-Ma2 encephalitis in association with breast cancer may present with rapid cognitive and behavioral changes in association with movement and sleep disorders. Normal CSF examination and brain imaging make limbic encephalitis less likely. Different types of antibodies were also tested negative; thus, making the possibility of prion disorders high on the list. The spectrum of movement disorders in this case deserves further characterization. First is the presence of semipurposeful repetitive hip flexion-extension movements associated with foot and less frequent hand rubbing resembling akathisia. While akathisia in our case is likely to be induced by olanzapine, it may occur as part of the agitation or nervousness, a common behavioral feature in prion diseases [3]. Specifically, akathisia may occur as a continuum of motor hyperactivation as part of a syndrome named agrypnic excitata (AE), which is a term to account for the association of slow wave sleep loss (“agrypnia”), and autonomic and motor overactivation (“excitata”) in patients with fatal familial insomnia (FFI) [2]. Together with resting tachycardia, it supports the presence of both autonomic and motor hyperactivation. Second is the recurrence of automatic gestures mimicking daily activities throughout the night including cycling, adjusting her pajamas, and pointing to non-existent objects. This feature probably represents oneiric stupor (OS), a peculiar behavior but useful diagnostic sign of AE [1]. A non-violent feature and the tendency to emerge at various times throughout the night distinguish OS from REM behavioral disorder (RBD). Recent polysomnographic study suggests that OS represents a state of unresponsiveness associated with dream-like mentation and appropriate motor behavior arising in the context of a completely disorganized sleep structure [1]. In addition to FFI, OS has been described in a number of disorders, including Morvan syndrome, delirium tremens, and sporadic Creutzfeldt-Jakob disease (CJD) of the VV2 subtype [1,4]. The presence of truncal ataxia,
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P. Panyakaew et al. / Clinical Neurology and Neurosurgery 137 (2015) 102–104
cycle and other autonomic functions, which could then disconnect the limbic cortical areas that involved in the control of instinctive behavior, and cognitive functions. However, in the absence of a positive family history, which is noted to be between 12 and 88% depending on the mutation types, the diagnosis of FFI can be difficult because of atypical clinical features and low sensitivity of diagnostic tests (CSF, EEG, and MRI are often normal or revealed nonspecific changes.) [6,7]. When clinically suspicious, the presence of unusual neuropsychiatric or cognitive illnesses should prompt treating physicians to consider prion disorders in the differential diagnosis, and proceed with relevant genetic testing. Recently, a scheme for the clinical diagnosis of FFI with a specificity of at least 80% was developed, which includes three items of organic sleep disturbances, CJD-like symptoms/signs, and relatively disease-specific symptoms/signs to allow the clinical suspicious of FFI no later than in the middle of the disease course [6]. This scheme further reinforces the fact that the clinical diagnosis of FFI is possible based on the careful observation of the clinical course, supported by VPSG and PET findings if available, and finally confirmed by the presence of a PRNP mutation on the genetic test. Fig. 2. The PRNP gene sequencing showed a missense GAC → AAC mutation at codon 178 while no mutation at codon 129 (Met) was observed.
Conflict of interest The authors have no conflict of interest.
gait instability, and myoclonus, which are also common movement disorders observed in various prion disorders, including CJD, Gerstmann-Sträussler-Scheinker, and FFI, does not help distinguish between different forms of prion disorders. The profession as the anesthetic nurse raises a slight possibility of iatrogenic CJD but she worked in a major university hospital, which employs standard disinfection methods for surgical instruments and biological products. The presence of autonomic, motor overactivation in conjunction with OS favors the possibility of FFI. Video polysomnographic (VPSG) study would be helpful in confirming our suspicious of FFI by demonstrating disruption of sleep-wake rhythm consisting of the disappearance of spindle delta activities, and the persistence of stage 1 non-REM sleep. REM sleep may persist but fails to stabilize appearing in short recurrent episodes during stage 1 NREM sleep [5]. Unfortunately, the test was not undertaken in the patient as the VPSG facility was not available locally. Although helpful, not all reported FFI cases in the medical literature have VPSG as a part of the diagnostic work-up and once organic sleep disturbances are evident, VPSG may not be considered as obligatory [6]. The analysis of genomic DNA showed a missense GAC → AAC mutation at codon 178 of PRNP gene resulting in the D178N substitution while no mutation at codon 129 (Met) was identified (Fig. 2). The finding (D178N, 129M) is consistent with the diagnosis of FFI. 4. Conclusion Our case provided many interesting learning points. First, the symptoms of insomnia were initially overlooked or trivialize into manifestations of anxiety and depression. Frequently neglected, fluctuating diplopia was also reported to be one of the common early manifestations of FFI [6]. Together with autonomic overactivity manifested as tachycardia, the clinical features implicate the dysfunction of the thalamus in the regulation of wake-sleep
Acknowledgment This study was supported by the Ratchadapiseksompoj Endowment Fund of Chulalongkorn University (RES560530136 & RES560530137-HR), research unit grant RA57/119 of Chulalongkorn University. We would like to thank Dr. Chanin Limwongse for his assistance with the genetic sequencing for a PRNP mutation. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.clineuro.2015.07. 001 References [1] P. Guaraldi, G. Calandra-Buonaura, R. Terlizzi, P. Montagna, E. Lugaresi, P. Tinuper, P. Cortelli, F. Provini, Oneiric stupor: the peculiar behaviour of agrypnia excitata, Sleep Med. 12 (Suppl. 2) (2011) S64–S67. [2] E. Lugaresi, F. Provini, Agrypnia excitata: clinical features and pathophysiological implications, Sleep Med. Rev. 5 (2001) 313–322. [3] A. Thompson, A. MacKay, P. Rudge, A. Lukic, M.C. Porter, J. Lowe, J. Collinge, S. Mead, Behavioral and psychiatric symptoms in prion disease, Am. J. Psychiatry 171 (2014) 265–274. [4] C. La Morgia, P. Parchi, S. Capellari, R. Lodi, C. Tonon, R. Rinaldi, S. Mondini, F. Cirignotta, ‘Agrypnia excitata’ in a case of sporadic Creutzfeldt-Jakob disease VV2, J. Neurol Neurosurg. Psychiatry 80 (2009) 244–246. [5] E. Sforza, P. Montagna, P. Tinuper, P. Cortelli, P. Avoni, F. Ferrillo, R. Petersen, P. Gambetti, E. Lugaresi, Sleep-wake cycle abnormalities in fatal familial insomnia evidence of the role of the thalamus in sleep regulation, Electroencephalogr. Clin. Neurophysiol. 94 (1995) 398–405. [6] A. Krasnianski, P. Sanchez Juan, C. Ponto, M. Bartl, U. Heinemann, D. Varges, W.J. Schulz-Schaeffer, H.A. Kretzschmar, I. Zerr, A proposal of new diagnostic pathway for fatal familial insomnia, J. Neurol. Neurosurg. Psychiatry 85 (2014) 654–659. [7] G.G. Kovacs, M. Puopolo, A. Ladogana, M. Pocchiari, H. Budka, C. van Duijn, S.J. Collins, A. Boyd, A. Giulivi, M. Coulthart, N. Delasnerie-Laupretre, J.P. Brandel, I. Zerr, H.A. Kretzschmar, J. de Pedro-Cuesta, M. Calero-Lara, M. Glatzel, A. Aguzzi, M. Bishop, R. Knight, G. Belay, R. Will, E. Mitrova, Eurocjd. Genetic prion disease: the EUROCJD experience, Hum. Genet. 118 (2005) 166–174.
